The RET proto-oncogene is often activated through somatic rearrangements in papillary thyroid carcinomas (PTCs). Three main rearranged forms of RET have been described: RET/PTC1 and RET/PTC3, which arise from a paracentric inversion and RET/PTC2, which originates from a 10 : 17 translocation. We previously developed a dual-color FISH test to detect these RET rearrangements in interphase nuclei of thyroid lesions. This approach allowed us to detect a novel translocation involving the RET region, which was not detectable by RT - PCR with specific primers for known rearrangements. A combination of RT - PCR and RACE analyses finally led to the identification of the fusion gene, which involves the 5' portion of PCM-1, a gene coding for a centrosomal protein with distinct cell cycle distribution, and the RET tyrosine kinase (TK) domain. FISH analysis confirmed the chromosomal localization of PCM-1 on chromosome 8p21-22, a region commonly deleted in several tumors. Immunohistochemistry, using an antibody specific for the C-terminal portion of PCM-1 showed that the protein level is drastically decreased and its subcellular localization is altered in thyroid tumor tissue with respect to normal thyroid. However, heterozygosity is retained for seven microsatellite markers in the 8p21-22 region, suggesting that the non-rearranged PCM-1 allele is not lost and that the translocation is balanced. Oncogene (2000) 19, 4236 - 4242